The gut and the brain communicate via the nervous system, hormones, microbiota-mediated substances, and the immune system. These intricate interactions have led to the term “gut-brain axis”. Unlike the brain—which is somewhat protected—the gut is exposed to a variety of factors throughout life and, consequently, might be either more vulnerable or better adapted to respond to these challenges. Alterations in gut function are common in the elder population and associated with many human pathologies, including neurodegenerative diseases. Different studies suggest that changes in the nervous system of the gut, the enteric nervous system (ENS), during aging may result in gastrointestinal dysfunction and initiate human pathologies of the brain via its interconnection with the gut. This review aims at summarizing the contribution of normal cellular aging to the age-associated physiological changes of the ENS. Morphological alterations and degeneration of the aging ENS are observed in different animal models and humans, albeit with considerable variability. The aging phenotypes and pathophysiological mechanisms of the aging ENS have highlighted the involvement of enteric neurons in age-related diseases of the central nervous system such as Alzheimer’s or Parkinson’s disease. To further elucidate such mechanisms, the ENS constitutes a promising source of material for diagnosis and therapeutic predictions, as it is more accessible than the brain.

Ginkgo biloba leaf extract EGb 761® has shown clinical efficacy in patients with mild cognitive impairment and dementia. However, the pharmacological action of EGb 761® in Alzheimer's disease (AD) remains unclear and molecular mechanisms targeted in the brain are not completely understood. We aimed to investigate 1) the potential sex-dependent effects of oral administration of EGb 761® in 5xFAD mice, an AD mouse model, and 2) the underlying microglial subtype responsible for the observed anti-inflammatory effects in the brain. Eight-week old 5xFAD and wild type mice received EGb 761®-supplemented diet or control diet for eight weeks. The study investigated changes in cognitive function as well as amyloid plaque load, expression of AD-related genes, and anti-inflammatory effects. Moreover, we used organotypic brain slices for confirmation and assessment of concentration-dependency of the observed EGb 761® effects and performed single cell RNA sequencing on the prefrontal cortex of male mice with focus on microglia. We demonstrate that EGb 761® treatment improves cognitive function in 5xFAD mice in several behavioral tests. Analysis of the brain tissue from these animals indicated a reduction in amyloid plaque load in the prefrontal cortex (PFC). This brain area was further investigated to assess the molecular changes that occurred following EGb 761® intake. Alterations in the expression of genes related to AD were highly sex-specific with effects on the cholinergic system, the γ-secretase complex, and neuroinflammation. Anti-inflammatory effects of EGb 761® with a particularly pronounced reduction of the TNFα-response could be shown for the PFC but also peripherally in the serum of 5xFAD mice of both sexes. Single-cell RNA sequencing revealed that EGb761® mainly affected disease-associated microglia stage 2 (DAM2), which are thought to have a detrimental role in AD. EGb 761® shows efficacy in the treatment of cognitive deficits in the 5xFAD mouse model via multimodal activity, including sex-specific and sex-unrelated mechanisms including the normalization of neuroinflammatory parameters.

The intestine is one of the first organs to show signs of aging, including cellular changes, microbiota shifts, and reduced regenerative capacity. The different components of the gut—such as the epithelium (which is directly exposed to a diverse array of host–microbe interactions), the microbiota itself, and the underlying enteric nervous system—likely contribute to aging in distinct ways. Understanding their individual and interactive roles is key to elucidating the mechanisms of intestinal aging. To better understand the contribution of individual components to intestinal aging, we analyzed gut tissue characteristics and compared these parameters with the composition and gene expression levels of colonic organoids by using two mouse strains: the aging‐resistant SAMR1 line and the SAMP8 line, which exhibit an accelerated aging phenotype. Here, we demonstrate that colonic organoids derived from these mice retain the age‐related characteristics of the colonic tissue, including changes in morphology and cellular composition. Furthermore, introducing the enteric nervous system into organoid culture revealed that the age of the epithelium exerts a more pronounced influence on the aging phenotype than the age of the innervating tissue. Interestingly, successfully delivering fecal extracts to organoids revealed that gut microbiota metabolites from aged animals resulted in an aging phenotype of the gut epithelium in vitro. In summary, our findings indicate the impact of aging on the gut epithelium and its interplay with the nervous system and microbiota. This may in future provide new strategies for slowing the aging process in the gut by manipulating the gut commensals.

The bidirectional communication between the gut microbiota, immune system, and central nervous system-the gut‒brain axis-plays a vital role in maintaining brain health. Its disruption can lead to neuroinflammation and cognitive decline. However, the relationship between the gut microbiota and age-related changes in brain immunity remains unclear. This study examined gut microbiota composition and T-cell profiles in senescence-accelerated SAMP8 mice and senescence-resistant SAMR1 controls at young adult and aged stages. The accelerated-aging phenotype of SAMP8 mice was confirmed by reduced behavioral performance and brain transcriptomic alterations. Fecal microbiota profiles were obtained using culture-dependent plating and 16S rRNA gene sequencing. T-cell phenotypes were determined by flow cytometry on brain and splenic leukocytes. Strain, age, and sex were drivers of microbiota composition variation. Microbial diversity differed between strains independently of age. Several bacterial genera had altered abundances in young SAMP8 mice, with only Intestinimonas remaining higher in aged SAMP8. T-cell profiling revealed strain- and age-specific immune signatures. In the brain, SAMP8 mice exhibited a higher CD4⁺/CD8⁺ ratio, and higher levels of pro-inflammatory cytokine-producing CD4⁺ T cells compared to SAMR1. In contrast, the spleens of SAMP8 mice had a lower CD4⁺/CD8⁺ ratio. Only the spleens of aged SAMP8 mice showed increased T-cell activation (effector/naïve ratios) and higher levels of pro-inflammatory cytokine-producing CD4⁺ and CD8⁺ T cells, suggesting age- and tissue-specific immune alterations. Nine bacterial genera correlated with immune cell frequencies and ratios. Notably, Intestinimonas showed a discordant association with the CD4⁺/CD8⁺ ratio in the brain (negative) and spleen (positive). Furthermore, CD8⁺ T cells correlated with microbiota composition variation more strongly than strain, age, and sex. Together, these findings link the gut microbiota to age-dependent immune remodeling in the brain and imply that altered microbial communities could influence pro-inflammatory T-cell responses, thereby contributing to accelerated brain aging.